Choline salts of steroid compounds and process of preparing same



-Wolffe'H. Feinstone, Indianapolis, Ind.

No Drawing. Application october 5, 1955 Serial No, 538,813 U Z-Claims.c1. zen-391.4

--This invention relates to choline salts of steroid compounds; andiinparticularto steroid compounds having estrogenic characteristics.

Estrone is effective when administered parenterally but has virtually nophysiological effect when administered orally. A naturally derivedcompound, sodium estrone sulfate, obtained from pregnant mares urine, isactive orally and quite stable. However, the commercial article isrelatively impure and probably owes its stability to the impurities.Sodium estrone sulfate prepared from synthetic estrone is known to beunstable and therefore has not found practical medical use.

One of the objects of this invention is to provide a compound which maybe produced from synthetically prepared estrone or related steroidcompounds, which is physiologically active upon oral administration, andstable.

Other objects will become apparent to those skilled in the art in thelight of the following disclosure.

In accordance with this invention generally stated a compound which maybe represented generally by the following structural formula isproduced.

r HO CHr-CE'r-N-OaSO CH3 CH:

These compounds may be considered as choline salts of the acid sulfateof a steroid compound in which the sulfate is attached to an enoliccarbon atom in the 7 position.

A specific example of a compound of this invention is choline estronesulfate, which may be represented as follows:

2,928,848 Patented Mai-.15,

ethylammonium hydroxide) in a 50% aqueous methanol solution were thenadded to the mixture. The mixture was warmed gently to completesolution. 2 N HCl was added drop-wise until the pH of the reactionmixture was 7.5. The reaction mixture was cooled in an ice bath. A heavycrystalline precipitate formed in about ten minutes. The crystals werefiltered oil? and washed with a small portion of a 50% aqueous solutionof methanol. The washed crystals were dried in a desiccator over calciumchloride. The yield of choline estrone sulfate was 550 mg. The motherliquor waspartially evaporated on a hot water bath and then cooled in anice bath to yield a second crop of crystals amounting to about 200 mg.

ious other ways, using estrone as the starting material.

fate or the acid sulfonyl chloride as by reacting it with chlorosulfonicacid. These, in turn can be reacted with choline base or cholinechloride in a suitable solvent to produce choline estrone sulfate.

O c1-it-0H+Ho -t CH: 3 I H 01-3-0 :0 or

CH3 3 I HO] H0.?O

o Estrone acid sulfate+choline basecholine estrone sulfate+H 0 Estroneacid sulfate-l-choline chloride choline estrone sulfate-i-l-lCl orEstrone sulfonyl chloride+choline basecholine estrone sulfate+HClVarious related estrogenic compounds may be used in place of estrone asstarting materials to produce corresponding choline (sulfate) salts. Forexample, equilenin; equilin; hippulin; 2-methyl-7-hydroxy-l.2-(A'-cyclopenteno)-l.2.3.4.9.l0.l1.l2-octahydrophenanthrene; 1- methyl 7hydroxy 1.2 cyclopentano 1.2.3.4 tetra hydrophenanthrene; 3.17 dihydroxyoestratriene; 3.17 dihydroxyoestrapentaene; Aoestratriene-3.16.17-triol; 1.3.5 estratrien 17 one 3.7.8 triol or 2methyl 7 hydroxy -l.2 cyclopentano1.2.3.4.9.l0.11.l2-octahydrophenanthrene. All of the foregoing compoundshave known definite physiological effects.

While the physiological effects of the following compounds have not beenestablished, to my knowledge, the following related compounds may beused to form the It is clear that the product can be synthesized in warcholine (sulfate) salt. For eeragnple: 17-methyl- A oestratrine 3 ol; A-pregnatrien-ol; 16-mi- A ergostahexaen- 3 o1; 7-hydroxy-3-ketothe 3')"pcsi'tien, at which esitien. the sulfate radicals attached. a

Having'tlius describedthe invention, Whit i sclainid and desired to besecured by Letters-Patent is? 1. Choline estrone sulfate.

2. The process of producing new therapeutic agents comprising the stepsof reacting, With choline ease; a compound taken from the groupconsisting of estronc acid sulfate, an alkali metal estrone sulfate andestrone sulfonyl chloride, and isolating the resultant choline estrcnesulfate.

References Cited in the file of this patent UNITED STATES PATENTS2,005,700 Johannessohn Iune'18, 1935 2,047,307 Butenandt July 14, 19362,178,109 Schwenk .a Oct: 31, 1939 2,305,727 Miescher' Dec. 22. 19422,597,723 Grant "L.'.r ;a-" May 20, 1952 2,636,042 Salkin .Q Apr. 21,1953 FOREIGN PATENTS 697,531 Great Britain Sept. 21?, 1953-

1. CHOLINE ESTRONE SULFATE.